Key Points • Rondaptivon pegol is a first-in-class prohemostatic molecule that prolongs the half-life of both endogenous FVIII and substituted FVIII.• Rondaptivon pegol could be used to enable once-weekly substitution therapy in severe hemophilia A or as prophylaxis in nonsevere hemophilia A.

Key Points The aptamer rondoraptivon pegol improved VWF/FVIII levels, multimer patterns, and thrombocytopenia in type 2B von Willebrand disease. Once weekly subcutaneous injections of rondoraptivon pegol may in the future be used for prophylaxis or treatment of VWD.

von Willebrand factor (VWF) and factor VIII (FVIII) circulate in a noncovalent complex in blood and promote primary hemostasis and clotting, respectively. A new VWF A1-domain binding aptamer, BT200, demonstrated good subcutaneous bioavailability and a long half-life in non-human primates. This first-in-human, randomized, placebo-controlled, double-blind trial tested the hypothesis that BT200 is well tolerated and has favorable pharmacokinetic and pharmacodynamic effects in 112 volunteers. Participants received one of the following: a single ascending dose of BT200 (0.18-48 mg) subcutaneously, an intravenous dose, BT200 with concomitant desmopressin or multiple doses. Pharmacokinetics were characterized, and the pharmacodynamic effects were measured by VWF levels, FVIII clotting activity, ristocetin-induced aggregation, platelet function under high shear rates, and thrombin generation. The mean half-lives ranged from 7-12 days and subcutaneous bioavailability increased dose-dependently exceeding 55% for doses of 6-48 mg. By blocking free A1 domains, BT200 dose-dependently decreased ristocetin-induced aggregation, and prolonged collagen-adenosine diphosphate and shear-induced platelet plug formation times. However, BT200 also increased VWF antigen and FVIII levels 4-fold (P<0.001), without increasing VWF propeptide levels, indicating decreased VWF/FVIII clearance. This, in turn, increased thrombin generation and accelerated clotting. Desmopressin-induced VWF/FVIII release had additive effects on a background of BT200. Tolerability and safety were generally good, but exaggerated pharmacology was seen at saturating doses. This trial identified a novel mechanism of action for BT200: BT200 dose-dependently increases VWF/FVIII by prolonging half-life at doses well below those which inhibit VWF-mediated platelet function. This novel property can be exploited therapeutically to enhance hemostasis in congenital bleeding disorders.

In March 2015, a few days after a major horse fair event in Bjelovar, Croatia, an equine influenza outbreak began and in the days that followed spread to more than 20 stud farms in the continental part of Croatia. The epidemiological investigation showed the importance of the national and international movement of asymptomatic carrier animals as a major risk factor for the introduction of the equine influenza virus and its spread in the naïve population. Molecular characterization and phylogenetic analyses confirmed that the EI outbreak was caused by an imported viral strain of the H3N8 subtype, phylogenetically similar to recent European strains belonging to Florida sublineage clade 2. The post-outbreak equine influenza seroprevalence in continental Croatia, based on ELISA testing, was 12.3% and varied between 1.1% and 32.6% on a county level. The highest seroprevalence in counties with predominantly sport and leisure horses highlighted animal management as a principal risk factor for equine influenza infection. On the other hand, variations in haemagglutination inhibition titres in the tested serum samples suggested different times of infection acquisition and unreported outbreaks of equine influenza in continental Croatia after the 2015 outbreak. Vaccination coverage, even after the large outbreak in 2015, was still below 10%, which suggests the lack of education of horse owners and represents a high risk for further outbreaks. In conclusion, influenza is a wide spread infection with multiple, often unrecorded, outbreaks in continental Croatia. A high risk of further outbreaks is present due to low vaccination coverage, an increase in the sport and leisure horse population and the intensive movement of those animals. In order to prevent *Corresponding author: Ljubo Barbić, PhD, DVM, Department of Microbiology and Infectious Diseases with Clinic, Faculty of Veterinary Medicine, University of Zagreb, Heinzelova 55, 10000 Zagreb, Croatia, Phone: +385 1 2390 211; Fax: +385 1 2390 211; E-mail: ljubo.barbic@vef.hr DOI: 10.24099/vet.arhiv.0033

Introduction: The commonest mitral regurgitation etiologies are degenerative (60%), rheumatic post-inflammatory, 12%) and functional (25%). Due to the large number of patients with acute MI, the incidence of ischaemic MR is also high. Ischaemic mitral regurgitation is a complex multifactorial disease that involves left ventricular geometry, the mitral annulus, and the valvular/subvalvular apparatus. Ischaemic mitral regurgitation is an important consequence of LV remodeling after myocardial infarction. Research Objectives: The objective of this study is to determine the role of echocardiography in detecting and assessment of mitral regurgitation mechanism, severity, impact on treatment strategy and long term outcome in patients with myocardial infarction during the follow up period of 5 years. Also one of objectives to determine if the absence or presence of ischaemic MR is associated with increased morbidity and mortality in patients with myocardial infarction. Patients and methods: The study covered 138 adult patients. All patients were subjected to echocardiography evaluation after acute myocardial infarction during the period of follow up for 5 years. The patients were examined on an ultrasound machine Philips iE 33 xMatrix, Philips HD 11 XE, and GE Vivid 7 equipped with all cardiologic probes for adults and multi-plan TEE probes. We evaluated mechanisms and severity of mitral regurgitation which includes the regurgitant volume (RV), effective regurgitant orifice area (EROA), the regurgitant fraction (RF), Jet/LA area, also we measured the of vena contracta width (VC width cm) for assessment of IMR severity, papillary muscles anatomy and displacement, LV systolic function ± dilation, LV regional wall motion abnormality WMA, LV WMI, Left ventricle LV remodeling, impact on treatment strategy and long term mortality. Results: We analyzed and follow up 138 patients with previous (>16 days) Q-wave myocardial infarction by ECG who underwent TTE and TEE echocardiography for detection and assessment of ischaemic mitral regurgitation (IMR) with baseline age (62 ± 9), ejection fraction (EF 41±12%), the regurgitant volume (RV) were 42±21 mL/beat, and effective regurgitant orifice area (EROA) 20±16 mm2, the regurgitant fraction (RF) were 48±10%, Jet/LA area 47±12%. Also we measured the of vena contracta width (VC width cm) 0,4±0,6 for assessment of IMR severity. During 5 years follow up, total mortality for patients with moderate/severe IMR–grade II-IV (54.2±1.8%) were higher than for those with mild IMR–grade I (30.4±2.9%) (P<0.05), the total mortality for patients with EROA ≥20 mm2(54±1.9%) were higher than for those with EROA <20 mm2(27.2±2.7%) (P<0.05), and the total mortality for patients with RVol ≥30 mL (56.8±1.7%) were higher than for those with RVol<30ml (29.4±2.9%) (P<0.05). After assessment of IMR and during follow up period 64 patients (46%) underwent CABG alone or combined CABG with mitral valve repair or replacement. In this study, the procedure of concomitant down-sized ring annuloplasty at the time if CABG surgery has a failure rate around 24% in terms of high late recurrence rate of IMR during the follow period especially after 18–42 months. Conclusion: The presence of ischaemic MR is associated with increased morbidity and mortality. Chronic IMR, an independent predictor of mortality with a reported survival of 40–60% at 5 years. Ischaemic mitral regurgitation has important prognosis implications in patients with coronary heart disease. Recognizing the mechanism of valve incompetence is an essential point for the surgical planning and for a good result of the mitral repair. It is important that echocardiographers understand the complex nature of the condition. Despite remarkable progress in reparative surgery, further investigation is still necessary to find the best approach to treat ischaemic mitral regurgitation.